The overall goal of this proposal is to elucidate the role of a novel function of elastin in the regulation of cell proliferation in the vascular system. Supravalvular aortic stenosis (SVAS) is an inherited obstructive vascular disease characterized by vascular smooth muscle cell hypertrophy. We have shown that familial SVAS is caused by point mutations in the elastin gene. In the preliminary data of this proposal, we have demonstrated that elastin gene mutations characteristic of SVAS result in reduced synthesis and deposition of elastin, and that this deficiency in elastin is associated with increased proliferation of fibroblasts and aortic smooth muscle cells from SVAS patients. Recently published evidence also suggests that GM1-gangliosidosis and Morquio B disease patients defective for a 67 kDa elastin binding protein (EBP) have a vascular phenotype that is very similar to SVAS. Based on these and additional lines of evidence, we hypothesize that in addition to conferring resilience to elastic tissues; elastin is also involved in regulation of cell proliferation and terminal differentiation of vascular cells. In this application, we propose to 1) analyze the mechanism of reduced elastin synthesis and deposition in SVAS, 2) investigate the role of insoluble elastin in the regulation of cell proliferation and apoptosis and 3) investigate the role of EBP in mediating cellular responses to elastin. In addition to offering an insight into the molecular basis of genetic forms of obstructive vascular diseases, the proposed work will also improve our understanding of more common forms of obstructive vascular disorders characterized by abnormal proliferation of vascular cells.